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OPFR Prioritization Using the Developmental Neurotoxicity In Vitro Test Battery: An Update to OECD IATA Case Study
Citation:
Oyetade, O., X. Chang, A. Kreutz, J. Hsieh, M. Behl, N. Sipes, D. Allen, AND H. Hogberg. OPFR Prioritization Using the Developmental Neurotoxicity In Vitro Test Battery: An Update to OECD IATA Case Study. SOT, Salt Lake City, UT, March 10 - 14, 2024. https://doi.org/10.23645/epacomptox.25988161
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Description:
Background and Purpose Organophosphorus flame retardants (OPFRs) are abundant and persistent in the environment due to their extensive use in industrial processes and products. In vivo and in vitro studies suggest that OPFRs may cause adverse health effects. Additionally, their similarity in structure to organophosphate pesticides,[WC1] presents a great concern for potential acute neurotoxicity and developmental neurotoxicity (DNT) commonly associated with organophosphates. However, current in vivo DNT guidelines (OECD TG 426 and 443) have challenges and limitations such as high costs, extensive timelines, and questionable human relevance. A DNT in vitro battery (DNT-IVB) was developed to help resolve these in vivo testing challenges. In September 2022, an OECD Integrated Approach for Testing and Assessment (IATA) case study was developed and published for DNT, with OPFRs as the case example, to demonstrate how applying DNT-IVB can prioritize a class of compounds. In the IATA case study, eight compounds were used, including aromatic OPFRs such as triphenyl phosphate (TPHP), isopropylated phenyl phosphate (IPP), 2-ethylhexyl diphenyl phosphate (EHDP), tricresyl phosphate (TMPP), isodecyl diphenyl phosphate (IDDP), tert-butylphenyl diphenyl phosphate (BPDP); halogenated (Tris(1,3-dichloro-2-propyl) phosphate (TDCIPP), tris(2-chloroethyl) phosphate (TCEP); as well as two classical [WC2] brominated flame retardants (BFRs), 2,2'4,4'-tetrabromodiphenyl ether (BDE-47) and 3,3',5,5'-tetrabromobisphenol A (TBBPA). Here, we enhance the OECD IATA case study, using the same chemicals with additional in vitro assay data, and contextualize the data with human exposure information,[WC3] and toxicokinetic (TK) parameters for relevant endpoints and mechanisms not covered in the initial case study. Methods The DNT-IVB consists of in vitro assays that evaluate processes in neurodevelopment and function (e.g., neural proliferation, neurite outgrowth, oligodendrocyte differentiation, cell migration, and neuronal firing/network formation). As an addition, behavioral data of complementary non-mammalian animal models, zebrafish and planaria, were included. We also added exposure data from new sources that sampled breast milk, urine, house dust, etc[WC4] ., to provide more thorough evaluation of human exposure to OPFRs. In vitro assay data were re-evaluated using the benchmark concentration (BMC) approach. Physiologically based pharmacokinetic (PBPK) modeling was performed to predict the maximum plasma concentration from exposure data to be compared to the in vitro BMCs. Furthermore, we collated additional information for endpoints and processes not covered in the current DNT-IVB, such as glia differentiation and function, ontogeny of neurotransmitters and receptors, and endocrine disruption from the literature. We also used curated high throughput screening data from the Integrated Chemical Environment (ICE) provided by the U.S. ToxCast and Tox21 initiatives that measured diverse endpoints. Results Considering compound class for the extended DNT-IVB endpoints, the classic BFRs and aromatic OPFRs were generally more active than halogenated OPFRs. Out of a total of 20 assays, BFRs and aromatic OPFRs were active in 10 assays on average, while halogenated OPFRs were active in 2-3 assays. The aromatic OPFR, BPDP, affected most of the endpoints with activity in 16 assays, while the classic BFR, BDE-47, was most potent with the lowest BMC, followed by other novel OPFRs, such as EHDP and TPHP. Of all the assays, behavioral and neurite outgrowth were most sensitive, with zebrafish showing more sensitivity in the behavior assays than the planaria species. Additionally, further characterizing the results of the DNT-IVB revealed that the in vitro BMC for many assays were within 10-fold, with only BDE-47 and TPHP observed as the more potent in the assays....
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DOI: OPFR Prioritization Using the Developmental Neurotoxicity In Vitro Test Battery: An Update to OECD IATA Case Study
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